I. Field of the Invention
This invention relates to pharmaceutically and veterinarily active compounds, which are derivatives of hydroxamic acid.
II. Description of the Prior Art
The compounds of the present invention act as inhibitors of metalloproteases involved in tissue degradation, such as collagenase, which initiates collagen breakdown, stromelysin (protoglycanase), gelatinase and collagenase (IV). There is evidence implicating collagenase as one of the key enzymes in the breakdown of articular cartilage and bone in rheumatoid arthritis (Arthritis and Rheumatism, 20, 1231-1239, 1977). Potent inhibitors of collagenase and other metalloproteases involved in tissue degradation are useful in the treatment of rheumatoid arthritis and related diseases in which collagenolytic activity is important. Inhibitors of metalloproteases of this type can therefore be used in treating or preventing conditions which involve tissue breakdown; they are therefore useful in the treatment of arthropathy, dermatological conditions, bone resorption, inflammatory diseases and tumour invasion and in thepromotion of wound healing. Specifically, compounds of the present invention may be useful in the treatment of osteopenias such as osteoporosis, rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration and tumour invasion.
A number of small peptide like compounds which inhibit metalloproteases have been described. Perhaps the most notable of these are those relating to the angiotensin converting enzyme (ACE) where such agents act to block the conversion of the decapeptide angiotensin I to angiotensin II a potent pressor substance. Compounds of this type are described in EP-A-0012401.
Certain hydroxamic acids have been suggested as collagenase inhibitors as in U.S. Pat. No. 4,599,361 and EP-A-0236872. Other hydroxamic acids have been prepared as ACE inhibitors, for example in U.S. Pat. No. 4,105,789, while still others have been described as enkephalinase inhibitors as in U.S. Pat. No. 4,496,540.
EP-A-0012401 discloses antihypertensive compounds of the formula: ##STR3## wherein R and R.sup.6 are the same or different and are hydroxy, alkoxy, alkenoxy, dialkylamino alkoxy, acylamino alkoxy, acyloxy alkoxy, aryloxy, alkyloxy, substituted aryloxy or substituted aralkoxy wherein the substituent is methyl, halo, or methoxy, amino, alkylamino, dialkylamino, aralkylamino or hydroxyamino;
R.sup.1 is hydrogen, alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups; PA1 substituted alkyl wherein the substituent is halo, hydroxy, alkoxy, aryloxy amino, alkylamino, dialkylamino, acrylamino, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio, carboxy, carboxamido, carbalkoxy, phenyl, substituted phenyl wherein the substituent is alkyl, alkoxy or halo; aralkyl or heteroaralkyl, aralkenyl or heteroaralkenyl, substituted aralkyl, substituted heteroaralkyl, substituted aralkenyl or substituted hetereoaralkenyl, wherein the substituent is halor or dihalo, alkyl, hydroxy, alkoxy, amino, aminomethyl, acrylamino, dialkylamino, alkylamino, carboxyl, haloalkyl, cyano or sulphonamido, aralkyl or hetereoaralkyl substituted on the alkyl portion by amino or acylamino; PA1 R.sup.2 and R.sup.7 are hydrogen or alkyl; PA1 R.sup.3 is hydrogen, alkyl, phenylalkyl, aminomethylphenylalkyl, hydroxyphenylalkyl, hydroxyalkyl, acetylaminoalkyl, acylaminoalkyl, acylaminoalkyl aminoalkyl, dimethylaminoalkyl, haloalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, mercaptoalkyl and alkylthioalkyl; PA1 R.sup.4 is hydrogen or alkyl; PA1 R.sup.5 is hydrogen, alkyl, phenyl, phenylalkyl, hydroxyphenylalkyl, hydroxyalkyl, aminoalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, mercaptoalkyl or alkylthioalkyl; PA1 R.sup.4 and R.sup.5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulphur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above, substituted with hydroxy, alkoxy or alkyl and the pharmaceutically acceptable salts thereof. PA1 R.sup.2 is C.sub.1 -C.sub.6 alkyl, benzyl, benzyloxybenzyl, (C.sub.1 -C.sub.6 alkoxy)benzyl or benzyloxy(C.sub.1 -C.sub.6 alkyl); PA1 a is a chiral centre with optional R or S stereochemistry; PA1 A is a ##STR5## or a --(CR.sup.3 .dbd.CR.sup.4)-- group wherein b and c are chiral centres with optional R or S stereochemistry; PA1 R.sup.3 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl or phenyl(C.sub.1 -C.sub.6 alkyl) and R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl(C.sub.1 -C.sub.6 alkyl), cycloalkyl or cycloalkyl(C.sub.1 -C.sub.6 alkyl). PA1 R.sup.1 represents a C.sub.2 -C.sub.5 alkyl group; PA1 R.sup.2 represents the characterising group of a natural alpha-amino acid in which the functional group can be protected, amino groups may be acylated and carboxyl groups can be amidated, with the proviso that R.sup.2 can not represent hydrogen or a methyl group; PA1 R.sup.3 represents hydrogen or an amino, hydroxy, mercapto, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 acylamino, C.sub.1 -C.sub.6 -alkylthio, aryl-(C.sub.1 -C.sub.6 alkyl)-, amino-(C.sub.1 -C.sub.6 -alkyl)-, hydroxy(C.sub.1 -C.sub.6 -alkyl)-, mercapto(C.sub.1 -C.sub.6 alkyl) or carboxy(C.sub.1 -C.sub.6 alkyl) group, wherein the amino, hydroxy, mercapto or carboxyl groups can be protected and the amino groups may be acylated or the carboxyl groups may be amidated; PA1 R.sup.4 represents hydrogen or a methyl group; PA1 R.sup.5 represents hydrogen or a C.sub.1 -C.sub.6 acyl, C.sub.1 -C.sub.6 alkoxy-C.sub.1 -C.sub.6 alkyl, di(C.sub.1 -C.sub.6 -alkoxy)methylene, carboxy, (C.sub.1 -C.sub.6 alkyl)carbinyl, (C.sub.1 -C.sub.6 alkoxy)carbinyl, arylmethoxy carbinyl, (C.sub.1 -C.sub.6 alkyl)amino carbinyl or arylamino carbinyl group; and PA1 R.sup.6 represents hydroxy or a methylene group; or PA1 R.sup.2 and R.sup.4 together represent a group-(CH.sub.2).sub.n --, wherein n represents a number from 4 to 11; or PA1 R.sup.4 and R.sup.5 together represent a trimethylene group; PA1 R.sub.2 is hydrogen or lower alkyl; PA1 R.sub.3 is lower alkyl or phenyl lower alkylene; PA1 R.sub.4 is hydroxy, lower alkoxy or hydroxyamino; and PA1 n is 1 or 2. PA1 R.sup.3 represents an amino acid side chain or a C.sub.1 -C.sub.6 alkyl, benzyl, (C.sub.1 -C.sub.6 alkoxy) benzyl, benzyloxy(C.sub.1 -C.sub.6 alkyl) or benzyloxybenzyl group; PA1 R.sup.4 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group; PA1 R.sup.5 represents a hydrogen atom or a methyl group; PA1 n is an integer having the value 0, 1 or 2; and PA1 A represents a C.sub.1 -C.sub.6 hydrocarbon chain, optionaly substituted with one or more C.sub.1 -C.sub.6 alkyl, phenyl or substituted phenyl groups; PA1 R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.4 alkyl, phenyl, thienyl, benzyl, acetyl or benzoyl group; PA1 R.sup.2 represents a C.sub.3 -C.sub.6 alkyl (for example isobutyl) group; PA1 R.sup.3 represents a benzyl or 4-(C.sub.1 -C.sub.6)alkoxyphenylmethyl or benzyloxybenzyl group; PA1 R.sup.4 represents a C.sub.1 -C.sub.4 alkyl (for example methyl) group; and PA1 R.sup.5 represents a hydrogen atom.
U.S. Pat. No. 4,599,361 discloses compounds of the formula: ##STR4## wherein R.sup.1 is C.sub.1 -C.sub.6 alkyl;
EP-A-0236872 discloses generically compounds of the formula ##STR6## wherein A represents a group of the formula HN(OH)--CO-- or HCO--N(OH)--;
and pharmaceutically acceptable salts of such compounds, which are acid or basic.
U.S. Pat. No. 4,105,789 generically discloses compounds which have the general formula ##STR7## and salts thereof, wherein R.sub.1 is hydrogen, lower alkyl, phenyl lower alkylene, hydroxy-lower alkylene, hydroxyphenyl lower alkylene, amino-lower alkylene, guanidine lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, imidazolyl lower alkylene, indolyl-lower alkylene or carbamoyl lower alkylene;
U.S. Pat. No. 4,496,540 discloses compounds of the general formula EQU A--B--NHOH
wherein A is one of the aromatic group-containing amino acid residues L-tryptophyl, D-tryptophyl, L-tyrosyl, D-tyrosyl, L-phenylalanyl, or D-phenylalanyl, and B is one of the amino acids glycine, L-alanine, D-alanine, L-leucine, D-leucine, L-isoleucine, or D-isoleucine; and pharmaceutically acceptable salts thereof.
It would however be desirable to improve on the solubility of known collagenase inhibitors and/or stomelysin inhibitors (whether as the free base or the salt) and, furthermore, increases in activity have also been sought. It is not a simple matter, however, to predict what variations in known compounds would be desirable to increase or even retain activity; certain modifications of known hydroxamic acid derivatives have been found to lead to loss of activity.